Leukemia is the most common pediatric cancer and the most common cause of disease-related death in childhood. Acute lymphoblastic leukemia (ALL) accounts for 80% of pediatric leukemias [
1]. The disease is characterized by uncontrolled proliferation of lymphoid progenitors in the bone marrow with consequent accumulation of malignant lymphoblasts in both bone marrow and peripheral blood. Current treatment regimens result in approximately 80% overall survival (OS) in children with ALL. However, the chemotherapeutic agents used target both malignant and non-malignant cells, and the side effects can be severe, especially for high-risk patients, who receive the most aggressive therapy [
1‐
3]. Particularly, long-term side effects are of great interest in pediatric oncology, since these patients are treated very early in life, with many years following their disease. The identification of additional markers which would allow improved risk stratification and more individually tailored therapy regimens is highly desirable, even to lower risk of adverse long-term side effects. For the time being the most important outcome predictors are genetic subsets, initial white blood cell count, age at diagnosis, and early treatment response measured by minimal residual disease (MRD) markers [
4]. Although many genetic abnormalities are associated with clinical outcome, only few of them are routinely used for treatment stratification. These include the presence of trisomy 4, 10 or 17 or the Philadelphia chromosome. Occasionally the significance of a given prognostic factor may change with advances in treatment. For example, the outcome for pediatric ALL patients with the Philadelphia chromosome has improved substantially since tyrosine kinase inhibitors were included in the treatment regimen [
5]. Finding markers for risk stratification can improve risk group assignment and consequently improve treatment efficacy by applying as much therapy as needed to cure the patient but avoiding over-treatment, which can increase long-term adverse side effects. Bcl-2 was initially identified as an anti-apoptotic regulatory protein [
6], but it also serves as an inhibitor of proliferation [
7]. The functional implication of Bcl-2 in tumorigenesis is ambiguous, as the anti-apoptotic effect may be oncogenic while the anti-proliferative effect appears tumor-suppressive. Which of the dual functions predominates seems to be tissue specific. This may explain why the prognostic implication of Bcl-2 expression depends on cancer type. For example, its expression is related to decreased survival in chronic lymphocytic leukemia and prostate cancer [
8,
9], whereas increased Bcl-2 expression is associated with favorable outcome in colorectal and breast cancer [
10,
11]. Bcl-2 may play a crucial role in the survival of hematolymphoid cells, where Bcl-2 inhibits apoptosis by preventing cytochrome c release from the mitochondria, thereby blocking caspase activation [
12].
BCL2 has two promoters with different functional properties. Transcription is driven by the P1 promoter, while the P2 promoter acts as a negative regulatory element [
13,
14].
Cis alterations have been shown to increase the activity of the P2 promoter, suppressing Bcl-2 expression [
14]. The functional−938 C > A promoter polymorphism is located in the inhibitory P2 promoter region [
15]. C and A alleles of this polymorphism differentially bind transcription factors and affect promoter activity. The C allele shows altered binding of transcription factors, increased activity of inhibitory promoter P2 and therefore decreased expression of Bcl-2. In patients with lymph node-negative breast cancer, oropharyngeal squamous cell carcinoma, chronic lymphocytic leukemia, glioblastoma multiforme and prostate cancer the A allele has been associated with higher Bcl-2 expression levels and the−938 C > A polymorphism has been associated with survival of patients suffering from these cancers [
16‐
20]. The present study investigates genotypes of the
BCL2−938 C > A promoter polymorphism as potential markers for risk and treatment stratification in children with ALL.